Systems Epigenomics of Persistent Bloodstream Infection

持续性血流感染的系统表观基因组学

• 批准号: 10551703
• 负责人: Michael R Yeaman
• 金额: $ 230.46万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551703
• 关键词: Acceleration; Address; Algorithms; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antifungal Agents; Antigens; Automobile Driving; Bacteremia; Bioinformatics; Blood; Blood Circulation; Candida; Candida albicans; Centers for Disease Control and Prevention (U.S.); Chromosomal Rearrangement; Clinical; Communicable Diseases; Computer Models; Computing Methodologies; DNA Methylation; Data; Data Set; Detection; Diagnostic; Disease; Disseminated candidiasis; Emergency Situation; Epigenetic Process; Etiology; Experimental Models; Fungemia; Gene Expression; Gene Rearrangement; Genetic; Genotype; Goals; Healthcare; Hematogenous; Hospital Mortality; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; In Vitro; Infection; Intensive Care Units; Intervention; Laboratories; Laboratory Study; Length of Stay; Libraries; Life; Macrophage; Mediating; Memory; Methods; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Nosocomial Infections; Organ; Outcome; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phenotype; Predisposition; Process; Productivity; Receptor Signaling; Refractory; Research; Research Project Grants; Resistance; Risk; STAT protein; STAT1 protein; Sepsis; Specificity; Staphylococcus aureus; Stress; Study models; System; Systems Biology; Technology; Testing; Therapeutic; Tissues; Training; Translating; United States National Institutes of Health; Variant; Virulence; Work; antimicrobial; antimicrobial drug; antimicrobial tolerance; biobank; candidemia; cell injury; chronic infection; complex data; cytokine; data management; effective therapy; epigenetic memory; epigenome; epigenomics; high risk; improved; in vivo; innate immune mechanisms; innovation; insight; methicillin resistant Staphylococcus aureus; methylomics; mortality; mouse model; neutrophil; novel; novel strategies; pathogen; pharmacologic; prediction algorithm; predictive modeling; prevent; programs; prospective; prototype; response; screening; sex; success; synergism; therapeutic candidate; vaccine strategy

PROJECT ABSTRACT Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti- infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise, in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence, there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors driving persistence outcomes. Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.

项目摘要 持续的血液感染是危及生命的传染病紧急情况，构成重大挑战。 为有效治疗干杯。当病原体在体外对抗感染剂敏感，但不敏感时，就会发生这种感染。 当适当使用该抗感染剂时，在体内的血液中被清除。因此，抗感染药物的使用 增加，加速抗感染耐药性惊人的增加。这种坚持驱使反 感染性升级驾驶耐药性是NIH高度优先关注的问题。由以下原因引起的血液感染 金黄色葡萄球菌(SA)或白色念珠菌(CA)越来越常见。急需关注的问题，高达35%的 耐甲氧西林金黄色葡萄球菌(MRSA)持续菌血症的患者即使接受黄金标准治疗也会屈服。同样， 在血源性播散性念珠菌病(HDC)患者中，总死亡率为39%， 重症监护病房，尽管接受了适当的治疗。一种疾病之谜是这种感染的核心：致病原因 在实验室测试中，病原体对抗菌剂敏感--但在人类身上不敏感。重要的是，坚持不懈 反映了一种独特的治疗类型--不同于传统抗生素耐药性的难治性感染。相反，坚持不懈 MRSA或CA是难以捉摸的：它们在体内以独特的方式适应宿主免疫反应和抗生素压力，然后恢复 在体外很快。目前，对于持续性MRSA或CA血流感染的治疗选择很少。因此， 了解人类、病原体和治疗因素之间的独特相互作用是一个关键的、尚未得到满足的需求 推动持久的结果。 根据我们广泛的初步数据，我们认为由MRSA和CA引起的持续感染是由 体内病原体、宿主免疫反应和抗菌剂的三向相互作用。我们假设 持久性分离株：1)有特定的表观基因组以实现持久性；2)颠覆先天免疫编程 和免疫逃避的记忆；3)唤起非保护性或适应不良的免疫反应；以及4)利用 上下文免疫力作为持久性储备库。我们进一步假设，临床上研究这一问题的传统方法 紧急现象还不足以理解它。我们已经开发了三个独立但协同的研究 项目以克服这些限制。每个项目都带来了经过验证的优势和创新的方法 具体目标，通过基于系统的方法进行协同，由杰出的技术、生物信息学和 计算核心。在这里，我们将使用最先进的技术来全面分析基因和 实验室研究和抗菌治疗背景下病原体和宿主免疫系统的表观遗传学 感染的实验模型。反过来，这些数据将使用强大的生物信息学和计算机技术进行分析 在大型复杂数据集中检测隐藏模式的方法。通过了解这些因素及其相互作用， 可以开发和应用新的方法来识别和治疗高危患者，以改善和挽救生命。这些 目标与国家卫生研究院和疾病控制与预防中心的优先事项理想地保持一致。